Host Pathogen Interactions in Invasive Aspergillosis

Overview

Invasive aspergillosis (IA) caused primarily by Aspergillus fumigatus is an emerging source of morbidity and mortality in developed countries including the United States. The frequency of invasive aspergillosis reflects disease states and treatments that result in prolonged neutropenia and immunosuppression. The rate of mortality with IA is 30-95%. Despite the accumulating evidence of the medical significance of this common mold, our understanding of its pathogenic mechanisms is limited. Epidemiological evidence demonstrates that concurrent host- and pathogen- mediated events govern the outcome of an A. fumigatus infection. Accumulated evidence supports the critical role of alveolar macrophage and neutrophils as the essential components of the innate immune system in preventing the establishment of an invasive infection in immune competent mammalian hosts. This host-pathogen interaction paradigm necessitates the integrated study of both systems to understand the molecular basis of invasive aspergillus disease. We have amassed the molecular, cellular, and bioinformatic tools required to mount a systematic analysis of the A. fumigatus host-pathogen interaction with the aim of chronicling crucial landmarks of disease initiation and progression. Our key hypothesis is that mechanisms employed by A. fumigatus in overcoming the defenses of the immune suppressed human host involve adapting the fungal metabolic pathways to iron depletion, alkaline shift, and nitrogen starvation as well as yet unknown lineage-specific pathways. Importantly, given the multifactorial nature of this interaction and the heterogeneity of the susceptible patient population, we are performing a parallel study of both the intact mammalian pathosystem and ex vivo immune cell-fungal interactions, in order to decipher stage-specific molecular landmarks of infection.

To characterize the A. fumigatus host-pathogen interaction, we are using two  approaches : in vitro macrophage and neutrophil infections of human cell lines; and mRNA expression profiles of infecting A. fumigatus conidia and germlings and infected host cells in culture.  This project will yield a wealth of information on the host-pathogen interactions necessary for A. fumigatus to mount a successful invasive infection as well as host immune system components necessary to maintain protective immunity against the invading fungus. The data generated will direct therapeutic approaches to treating, and diagnosing these invasive infections. The host response analysis will identify approaches to modulate or augment the therapeutic regimens applied concurrently with transplant and other medical interventions in order to minimize the risk of invasive aspergillosis during and after these treatments.